Primary biliary cirrhosis (PBC) is a chronic, slowly progressive, liver disease of unknown etiology. There is no known effective treatment, PBC is ultimately fatal and permanent remissions are not reported. Excessive copper accumulation in the liver and associated immunoserologic abnormalities suggest that abnormal copper metabolism and immunological mechanisms may be involved in the pathogenesis of this disease. Experience in our institution as well as elsewhere suggest that PBC may be more common that previously recognized. The objectives of this investigation are to continue a double-blind, randomized, controlled trial evaluating the therapeutic efficacy of D-penicillamine, and as part of this study to investigate the pathogenesis of this disease. To achieve the latter, we propose to define the physiologic state of copper in bile and to study biliary copper secretion. Furthermore, in other ancillary studies we plan to investigate the mechanism of in vitro cytotoxicity of circulating mononuclear cells for autologous hepatocytes in these patients. Favorable patient referral to this center affords a unique opportunity to conduct a therapeutic trial and to investigate promising mechanisms which may relate to pathogenesis. Sixty-five patients with well-defined PBC have already been enrolled, so that we have probably the largest single group of patients with this disease in the United States. Further, patient compliance is extremely high so that excellent adherence to the protocol is maintained.